MCM8 promotes gastric cancer progression through RPS15A and predicts poor prognosis.

BACKGROUND: Gastric cancer (GC) is the fourth leading cause of cancer-related death worldwide. Minichromsome maintenance proteins family member 8 (MCM8) assists DNA repair and DNA replication. MCM8 exerts tumor promotor function in multiple digestive system tumors. MCM8 is also considered as a potential cancer therapeutic target. METHODS: Bioinformatics methods were used to analyze MCM8 expression and clinicopathological significance. MCM8 expression was detected by immunohistochemistry (IHC) staining and qRT-PCR. MCM8 functions in GC cell were explored by Celigo cell counting, colony formation, wound-healing, transwell, and annexin V-APC staining assays. The target of MCM8 was determined by human gene expression profile microarray. Human phospho-kinase array kit evaluated changes in key proteins after ribosomal protein S15A (RPS15A) knockdown. MCM8 functions were reassessed in xenograft mouse model. IHC detected related proteins expression in mouse tumor sections. RESULTS: MCM8 was significantly upregulated and predicted poor prognosis in GC. High expression of MCM8 was positively correlated with lymph node positive (p < 0.001), grade (p < 0.05), AJCC Stage (p < 0.001), pathologic T (p < 0.01), and pathologic N (p < 0.001). MCM8 knockdown inhibited proliferation, migration, and invasion while promoting apoptosis. RPS15A expression decreased significantly after MCM8 knockdown. It was also the only candidate target, which ranked among the top 10 downregulated differentially expressed genes (DEGs) in sh-MCM8 group. RPS15A was identified as the target of MCM8 in GC. MCM8/RPS15A promoted phosphorylation of P38α, LYN, and p70S6K. Moreover, MCM8 knockdown inhibited tumor growth, RPS15A expression, and phosphorylation of P38α, LYN, and p70S6K in vivo. CONCLUSIONS: MCM8 is an oncogene and predicts poor prognosis in GC. MCM8/RPS15A facilitates GC progression.

Quercetin induces ferroptosis in gastric cancer cells by targeting SLC1A5 and regulating the p-Camk2/p-DRP1 and NRF2/GPX4 Axes.

Quercetin (Quer) is a natural flavonoid known for its inhibitory effects against various cancers. However, the mechanism by which Quer inhibits gastric cancer (GC) has not yet been fully elucidated. Ferroptosis, a mode of programmed cell death resulting from lipid peroxidation, is regulated by abnormalities in the antioxidant system and iron metabolism. Through flow cytometry and other detection methods, we found that Quer elevated lipid peroxidation levels in GC cells. Transmission electron microscopy confirmed an increase in ferroptosis in Quer-induced GC. We demonstrated that Quer inhibits SLC1A5 expression. Molecular docking revealed Quer's binding to SLC1A5 at SER-343, SER-345, ILE-423, and THR-460 residues. Using immunofluorescence and other experiments, we found that Quer altered the intracellular ROS levels, antioxidant system protein expression levels, and iron content. Mechanistically, Quer binds to SLC1A5, inhibiting the nuclear translocation of nuclear factor erythroid 2-related factor 2 (NRF2), resulting in decreased xCT/GPX4 expression. Quer/SLC1A5 signaling activated p-Camk2, leading to upregulated p-DRP1 and enhanced ROS release. Additionally, Quer increased the intracellular iron content by inhibiting SLC1A5. These three changes collectively led to ferroptosis in GC cells. In conclusion, Quer targets SLC1A5 in GC cells, inhibiting the NRF2/xCT pathway, activating the p-Camk2/p-DRP1 pathway, and accelerating iron deposition. Ultimately, Quer promotes ferroptosis in GC cells, inhibiting GC progression. Overall, our study reveals that Quer can potentially impede GC progression by targeting SLC1A5, offering novel therapeutic avenues through the modulation of ferroptosis and iron homeostasis.